The role of cyclooxygenases in endotoxin- and interleukin-1-induced hypophagia

Endotoxin (lipopolysaccharide, LPS) and interleukin-1 (IL-1) reduce food intake in rodents. Cyclooxygenase (COX) inhibitors have long been known to attenuate these responses, but recent work has revealed the existence of two distinct isoforms of the enzyme, COX1 and COX2, with different characteristics and functions. Therefore, we reassessed the COX involvement using inhibitors with different selectivities for COX1 and COX2. Feeding was assessed in nondeprived mice by measuring the intake of sweetened milk in a 30-minute period, as well as daily food pellet intake. LPS and IL-1beta consistently reduced milk intake. Treatment of the mice with the selective COX1 inhibitor, piroxicam, attenuated the hypophagic responses to IL-1 and LPS. Similar results were obtained with diclofenac. The hypophagic responses to LPS and IL-1beta were not affected by the COX2-selective inhibitors nimesulide and NS-398 at doses considered selective for COX2, but were inhibited by higher doses. Pretreatment of the mice with aspirin, an irreversible inhibitor of COX1 and COX2, prevented the hypophagic response to IL-1, 16 h, but not 40 h later. Taken together, these results suggest that COX1 may be the major isozyme involved in the hypophagic responses to LPS and IL-1, but a role for COX2 cannot be excluded. We also studied the combination of a COX inhibitor with the IL-1 receptor antagonist protein. Consistent with earlier results, both the IL-1 receptor antagonist (IL-1ra) and indomethacin attenuated the hypophagic responses to LPS. Combination of the two treatments produced additive results almost completely preventing the hypophagic response. Because indomethacin almost completely prevented the hypophagic response to IL-1, this additivity suggests that there are multiple mechanisms by which LPS induces hypophagia.